In primary cultures of mesencephalic neurons stimulation of non-NMDA type receptors destabilizes Ca2+ homeostasis earlier in dopaminergic neurons than in other neurons. Exposure of cell cultures in 10 muM AMPA, glutamate, kainate or quisqualate for 1-5 min increased [Ca2+]i by 2 to 3 fold in dopaminergic, and non-dopaminergic neurons. Superfusion with agonist-free incubation buffer brought [Ca2+]i back to control levels in both cell types. Exposure to 50 muM of the same acids increased [Ca2+]i levels in dopaminergic neurons by 3-5 fold and cell death occurred 6-7 hrs after exposure. In contrast, the rise in [Ca2+]i in non-dopaminergic neurons was reversed by wash-out. Preincubation of cultured neurons with nifedipine (a voltage-dependent Ca2+ channel blocker), NBQX (an AMPA receptor antagonist), or dantrolene (a blocker of Ca2+-dependent Ca2+ release from intracellular stores) prevented the destabilization of Ca2+ homeostasis in dopamergic neurons. In dopaminergic neurons Ca2+ overload was triggered by activation of glutamate- and voltage-gated channels, as well as increased release of Ca2+ from intracellular stores.